Introduction
Bronchial asthma is a common chronic airway inflammatory disease that causes substantial economic and social burdens [
1,
2]. Global Initiative for Asthma (GINA) proposes that the long-term goal of asthma treatment is to achieve symptom control and reduce the risk of acute exacerbations, irreversible airflow limitation, and treatment side effects [
3]. At the same time, assessment, adjustment, and monitoring form a continuous cycle in asthma treatment and management strategy. Thus, effective self-assessment and monitoring are vital for asthma patients to achieve long-term treatment goals [
4]. However, previous studies have shown that the natural history of asthma is heterogeneous and complex, characterized by circadian rhythms and long-term dynamic changes [
5]. Therefore, daily asthma management should include dynamic changes, not just the absolute value of a single measurement.
Studies have shown inconsistencies in symptoms, lung function, and airway inflammation of asthma patients [
6]. Self-management based on symptoms and peak expiratory flow (PEF) may still miss patients at risk of severe acute exacerbations in the future [
7,
8]. There are also inconsistencies between physician and patient in the assessment of asthma control [
9]. So, perhaps more methods are needed for daily asthma assessment. Fractional exhaled nitric oxide (flow of 50 mL/s, Fe
NO50) is one of the tools to assess airway inflammation, which is non-invasive, simple, rapid, and is currently mainly used in hospital scenarios [
10]. Studies have shown that increasing the number and frequency of Fe
NO50 monitoring helps predict asthma control status [
11]. The daily fluctuation of Fe
NO50 with different asthma control statuses is different [
12]. Studying the long-term variation pattern of Fe
NO50 measurements makes it possible to identify the risk of acute exacerbations [
13‐
15]. Simultaneous daily monitoring of Fe
NO50 can also assess compliance [
10,
16,
17] and responsiveness to inhaled corticosteroids (ICS) for Type 2 asthma [
18‐
21]. In summary, applying Fe
NO50 in daily asthma self-monitoring may be significant for asthma management.
More convenient products are applied to self-monitor chronic diseases with the development of science and technology and improved economic levels [
7]. The emergence of daily home monitoring devices and innovative applications has made it possible to monitor circadian rhythms and daily changes for asthma patients. However, whether asthma patients could benefit from it is not fully known due to the lack of prognostic data [
22]. We attempted to analyze the pattern of longitudinal dynamic changes in Fe
NO50 after treatment in uncontrolled asthmatic patients who were not regularly treated. To initially explore the value of Fe
NO50 domiciliary monitoring in the daily management of asthma.
Methods
Subjects
Twenty-two asthma patients who visited the respiratory outpatient of China-Japan Friendship Hospital from October 2019 to December 2021 were prospectively included.
Inclusion criteria: (1) age ≥ 18 years old; (2) fulfilled the diagnostic criteria of bronchial asthma defined by GINA 2018 [
3]; (3) asthma symptom control was assessed as uncontrolled according to GINA2018 [
3].
Exclusion criteria: (1) subjects underwent other interventional clinical trials 30 days before enrollment; (2) subjects with other pulmonary diseases or other severe system diseases that may affect the conduct of the study; (3) subjects with a smoking index > 10 pack-years and a history of smoking for nearly one year; (4) subjects had been on regular asthma therapy within 12 weeks before enrollment; (5) subjects had respiratory tract infection within four weeks before enrollment.
Written informed consent was obtained from each participant. The China-Japan Friendship Hospital ethics committee approved this study (No. 2018-19-k14, approval date: February 6th, 2018).
Study design
Enrollment stage: All subjects performed the asthma control test (ACT) [
23], mini-asthma quality of life questionnaire (mini-AQLQ) [
24], differential blood count, serum total IgE (enzymatic chemiluminescence, Beckmen Coulter, USA), spirometry, Fe
NO50 (NIOX Vero, Circassia (Beijing) Medical Device Co., Beijing, China), differential induced sputum count. Mobile spirometry (A1, Breath Home, China) [
25] and Fe
NO50 monitor (NIOX Vero, Circassia (Beijing) Medical Device Co., Beijing, China) were provided to each subject to measure Fe
NO50 and mSpirometry twice a day over four weeks at home. On the day of enrollment, subjects were trained on using the equipment mentioned above (viewing usage videos and on-site instruction). Subjects were contacted during subsequent use to ensure they correctly mastered the usage methods.
The treatment strategy is not affected by the study, and the patient's treatment plan is formulated by the physician, with medication recommendations based on the GINA 2018 guidelines [
3].
Domiciliary monitor stage: Subjects were asked to measure FeNO50 and mSpirometry twice daily during the same period, between 06:00 to 08:00 and 20:00 to 22:00, respectively. Before medication, FeNO50 measurement was first taken, and the results were automatically recorded on the monitor. When the subjects returned the device, all measurements were transmitted to the computer. Mobile spirometry was taken three times, and the best of the three readings were automatically uploaded to an electronic diary card. Peak expiration flow (PEF), forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), the maximum expiratory flow rate at 75%/50%/25% of the vital capacity (MEF75, MEF50, and MEF25) were collected by mSpirometry.
End of follow-up: ACT, mini-AQLQ, spirometry, FeNO50, differential blood, and induced sputum count were reviewed again.
Statistical Analysis
The normal distribution data were represented by mean ± standard deviation (sd). Non-normally distributed data were shown as median (interquartile range, IQR). A comparison of each measure before and after follow-up was performed using paired samples t-test and Wilcoxon signed-rank test. The categorical variables were expressed by frequency (composition ratio or percentage) and compared by the chi-square test.
Indicators and calculation formulas representing the variation of FeNO50 and mSpirometry: diurnal variation rate = (highest in a day - lowest in a day)/ (mean of highest versus lowest in a day)×100; mean daily variation rate = mean of diurnal variation rate over 1week; weekly variation rate = (highest over two weeks - lowest over two weeks)/ (mean of highest versus lowest over two weeks)×100.
A repeated-measures analysis of variance was used to compare diurnal differences in Fe
NO50 logarithmic transformed values and mSpirometry. The least-square method was used to perform curve fitting for each subject's daily monitoring results of Fe
NO50 and mSpirometry, and the second derivative was used to calculate the inflection point. The inflection point in this study was the transition point for the improvement of Fe
NO50 and mSpirometry, and its progress slowed down after the inflection point. The relative plateau of treatment was defined as the time to reach the inflection point [
26]. The effect-acting time was calculated with a Fe
NO50 reduction of more than 20% and an improvement in mSpirometry of more than 10% as criteria [
10,
27]. ANOVA and Friedman's test were used to compare the relative plateau and the effect-acting of treatment between Fe
NO50 and mSpirometry. Friedman's test was also used to compare the differences in variation rates of Fe
NO50 and mSpirometry. A two-tailed
p-value of < 0.05 was considered significant. All statistical analyses were performed with SPSS 20 (IBM-SPSS, Armonk, NY, USA) and Matlab software (Mathworks, Inc., Natick, MA, USA).
Discussion
Through daily domiciliary monitoring of untreated, uncontrolled asthmatic patients, we found significant diurnal differences and daily dynamic changes in FeNO50 and mSpirometry, which can be used to evaluate asthma patients' response to treatment and condition assessment.
Fe
NO50 is a sensitive biomarker that reflects the inflammation of airway eosinophils [
28]. In the early stage of treatment, Fe
NO50 was significantly higher in the morning than at night in asthmatic patients, consistent with previous findings [
21,
29]. Although studies have shown that the decrease of FEV
1 affects the results of Fe
NO50, the effect of the change in airway diameter on Fe
NO50 will be offset when the airway inflammation is higher [
30,
31]. However, the disappearance of diurnal differences in asthmatic patients after treatment may be related to airway inflammation and lung function improvement [
32,
33].
The primary purpose of this study is to observe the impact of home monitoring on evaluating treatment outcomes. After four weeks of treatment, all participants showed improvement in symptoms and inflammation levels. Therefore, although different treatment plans may cause biases, we believe the impact on the conclusion is relatively tiny.
Peak-trough times of lung function and biomarkers in asthma patients may differ due to individual chronotype differences [
34]. Lung function fluctuates between 6-7 days in Fig.
1, but there is no significant difference. Although the measurement period was specified to avoid bias, the personal measurement time or additional measurement period was not selected according to the living habits, thus reducing the reliability of dynamic variation. No significant diurnal differences in lung function were found in this study, which may be related to the relatively good lung function of the included subjects, reducing the sensitivity of diurnal differences.
We characterized the changing trend of Fe
NO50 in treated Type 2 asthmatic patients. We found that Fe
NO50 could detect the treatment response for 3-5 days and reached a relative plateau for two weeks. Various indices (PEF, FEV1, MEF
75, MEF
50, MEF
25) of mSpirometry improved gradually, with treatment effect-acting time around 8~12 days and reached a relative plateau of improvement around 2-3 weeks [
26,
35]. However, due to the relatively low goodness of fit of the fitting curves for mSpirometry in this study, the treatment turning point of mSpirometry still needs further validation with extensive sample data.
Daily monitoring found that the treatment effect assessed by Fe
NO50 was significantly earlier than mSpirometry, and the time to reach the relative plateau of treatment was substantially earlier than FEV
1. As we can see, Fe
NO50 was more sensitive than mSpirometry in assessing responsiveness to asthma therapy. Meanwhile, the latest research indicates that Fe
NO50 is a risk biomarker identifying patients at increased risk of lung function decline [
36].
After treatment, the daily and weekly variation rates of FeNO50 and mSpirometry showed a decreasing trend. Our study found that the average daily variation of FeNO50 in the first week was significantly higher than in the fourth week. Therefore, the improvement of diurnal variation in FeNO50 can also be used to evaluate the effectiveness of treatment in asthma. This variability over time suggests that the domiciliary monitoring strategy has the advantage of detecting daily and long-term changes in physiology and inflammation, providing substantial evidence to predict future exacerbations and disease assessment. After four weeks of treatment, the participants showed significant improvements in asthma control, quality of life, lung function, and inflammation. With the considerable improvement of symptoms and clinical indicators, the variation rate of domiciliary monitors gradually decreased, which is an essential clinical signal to evaluate the changes in the conditions of asthma patients.
The study had limitations. Firstly, as our study is a pilot study, all admitted patients were untreated type 2 asthma. We did not include patients with severe asthma. Still, previous studies have shown that Fe
NO50 can also serve as an inflammatory marker for evaluating treatment response in severe asthma populations. [
37]. A large sample study was needed to demonstrate the general generalization of the variation pattern. Secondly, complex device use, frequency of daily readings, and strict monitoring times reduce the completion of measures [
38,
39]. Still, previous studies have also shown that remote monitoring devices allow subjects to understand their self-control levels and improve patient compliance [
40,
41]. Although there was no monitoring of drug adherence, the completion rate of this study exceeded 80%, indirectly indicating that drug adherence is still acceptable. Thirdly, our study could not compare mSpirometry A1 with the lung function laboratory device. The study found that only a portion of mSpirometry A1 (BreathHome, China) met the quality and performance evaluation standards [
25]. However, considering this study mainly observed dynamic changes, the research results are still acceptable.
In conclusion, this pilot study of domiciliary monitoring found that FeNO50 in uncontrolled asthma patients has significant diurnal differences and is superior to mSpirometry in assessing sensitivity to treatment response. The dynamic fluctuation of FeNO50 may be available for evaluating disease conditions in asthmatics. Studies with large samples and long observation periods are expected to explore mobile domiciliary monitors in asthma management.
Acknowledgments
Thanks to Hongyi Wang (Circassia (Beijing) Medical Device Co., Beijing, China), Yang Wang (Circassia (Beijing) Medical Device Co., Beijing, China, and Yang Dong (Breath Home, Beijing, China) provided technical help.
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